NMJ Flashcards
What does the somatic nervous system activate?
Skeletal muscle contraction
How is the somatic nervous system regulated?
By corticospinal tracts and spinal reflexes
Somatic synapses?
One at NMJ - ACh –> nicotinic receptor
Parasympathetic synapses?
Long preganglionic - ACh –> nicotinic receptor
Short postganglionic - ACh –> muscarinic receptor
Sympathetic synapses?
Short preganglionic - ACh –> nicotinic receptor
Long postganglionic - NE –> adrenergic receptors
(sweat glands ACh –> muscarinic)
What does the autonomic nervous system activate?
Smooth muscle
Exocrine glands
Cardiac tissue
Metabolic activities
How is the autonomic nervous system regulated?
By brain stem centres
Outline the structure of a nicotinic receptor
Ligand gated ion channel
Requires the binding of 2 ACh molecules.
5 subunits.
Upon binding, the 2nm channel opens wider due to conformational changes.
Composition of NM/N1 form?
a1 x 2
b1
delta
epsilon (gamma in embryonic)
Composition of NN/N2 form?
a2-10
b2-4
What is the NMJ?
Specialised form of synaptic transmission between neurons and skeletal muscle to cause muscle contraction
What causes the release of neurotransmitter?
Motor neuron depolarisation causes the action potential to travel down the nerve fibre to the NMJ.
Depolarisation of the axon terminal causes an influx of Ca2+
Triggers fusion of synaptic vesicles and release of ACh (neurotransmitter)
What does the neurotransmitter cause?
ACh binds to postsynaptic ACh receptor on the muscle fibre at the motor end plate
Binding opens the channels, causing an influx of sodium ions.
Depolarisation occurs on the sarcolemma and travels down the T tubules to cause the release of Ca2+ from the sarcoplasmic reticulum - contraction
What happens to the ACh?
Ubound ACh diffuses away or is hydrolysed by AChE
Outline Myasthenia gravis?
Autoantibodies to the nicotinic ACh receptors on the motor end plates of muscles. Binding of ACh is blocked. Also induce complement-mediated degradation of the receptors, resulting in progressive weakening of the skeletal muscles.
Autoantibodies to MuSK which is important for the tight clustering of receptors at the NMJ
Symptoms of Myasthenia gravis?
Weakness of eye muscles, swallowing and slurred speech.
Eye movement, facial expressions, chewing, talking, swallowing.
Breathing and neck movements.
Describe Lambert-Eaton myasthenic syndrome?
Autoantibodies to presynaptic voltage gated calcium channel (VGCC)
Interfere with the calcium dependent release of ACh from the presynaptic membrane and cause a reduced endplate potential on the postsynaptic membrane
Describe Neuromyotonia (Isaac’s syndrome)?
Autoantibodies to presynaptic voltage gated potassium channels (VGKC).
Results in continuous excitability.
Main drugs involved at NMJ?
ACh blocking agents
Anticholinesterases (increases ACh - all others block/decrease)
Drugs affecting synthesis and storage of axonal ACh
Active compound in curare?
d-tubocararine
skeletal muscle paralysis
blocks ACh binding to the receptor
Non depolarising blocking agent.
Subclasses of neuromuscular blocking drugs?
Depolarising and non-depolarising
Mechanism of non depolarising blockers?
Prevents the opening of the channel when it competitively binds to the receptor.
Can be reversed.
Rocuronium?
Non depolarising blocker
Mechanism of depolarising blockers?
Occupy the receptor site, opening the channel and block the channel.
Normal closure of the gate is prevented and the blocker can move into the pore.
May desensitise the end plate by causing persistent depolarisation
Succinylcholine?
Depolarising blocker
Cobratoxin and a-bungarotoxin?
Bind with high affinity to the nicotinic receptors, causing a postsynaptic block at the NMJ
Effects of NMJ blocking agents?
Paralysis from the small rapidly moving muscles to limbs then respiratory muscles
Non depolarising agents effect?
Flaccid, relaxed paralysis.
Can be reversed by AChE inhibitors.
Histamine release.
Muscarinic blocking.
Depolarising agents effect?
Phase 1 - membrane depolarisation, transient fasiculations –> paralysis
Phase 2 - desensitisation. Membrane depolarises and is hypersensitive to ACh. Block can’t be reversed
Pancuronium?
Non depolarising blocking agent
Gallamine?
Non depolarising blocking agent
Mlvacurium?
Non depolarising blocking agent
Atracurium?
Non depolairising blocking agent
Clinical uses of NMJ blocking agents?
Muscle relaxation in surgety Orthopedics Facilitate intubations Facilitate internal exams Prevent trauma Diagnostic
Uses of acetylcholinesterase inhibitors?
Myasthenia gravis treatment Alzheimer's Lewy body dementia Glaucoma Antidote for anticholinergic poisoning
Types of acetylcholinesterase inhibitors?
Venoms & poisons
Nerve agents & insecticides
Examples of acetylcholinesterase inhibitors?
Edrophonium
Neostigmine
Pyridostigmine
Distigime
Symptoms of NMJ overstimulation?
Vasodilation Sweating Salivation Bronchial secretions Miosis Flaccid paralysis Respiratory failure.
Nerve gas poisoning?
Atropine - antidote, blocks ACh from binding
Oximes can regenerate the enzymes
Organophosphates?
Irreversible acetylcholinesterase inhibitors
phosphorus atom covalently binds to a serine hydroxyl group in the active site
pralidoxime reactives the enzmye
Neostigmine?
AChE inhibitor which permits buildup of ACh for more intensive and prolonged activation.
Time prolonged to interact with receptors that are not blocked by autoantibodies
Edrophonium?
Readily reversible AChE inhibitor.
True competitive inhibition.
Can be used to differentiate myasthenic from cholinergic crisis.
Myasthenic crisis?
Not enough NM stimulation.
Edrophonium will reduce muscle weakness by supplying more ACh
Cholinergic crisis?
Too much NM stimulation.
Will make weakness worse by inducing a depolarising block.
Physostigmine?
Reversible pseudocompetitive AChE inhibitor.
Treat myasthenia gravis, Alzheimer’s and delayed gastrice emptying
Crosses BBB
AChE inhbitors to treat dementia?
hypothesis - cognitive decline is linked to hippocampus and cortex.
SNARE proteins?
allow vesicles to release AC into NMJ.
Botox cleaves specific SNARE proteins to block the vesicles from releasing ACh.
